The present invention is concerned with a process for synthesizing intermediate compounds useful for preparing compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as compound J in the examples below. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
The invention described herein concerns synthesis of 4-tert-butyloxycarbonyl-(S)-piperazine-2-tert-butyl-carboxamide 1 of the structure, ##STR1## which is an intermediate for the synthesis of the clinically efficacious compound J, of the structure ##STR2##
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. The end product compounds, including certain oligopeptide analogs that can be made from the novel intermediates and processes of this invention, are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993. See, for example, Compound J therein.
Previously, the synthesis of compound J and related compounds was accomplished via a 12-step procedure described in EP 541,168. In the process, 4-tert-butyloxy-carbonyl-(S)-piperazine-2-tert-butylcarboxamide is prepared in a classical resolution of the racemic piperazine-2-tert-butylcarboxamide. The undesired (R) enantiomer is racemized in a separate step and recycled. The process is summarized in Scheme I: ##STR3##
Although the process is high yielding and efficient, it requires a multitude of operations to resolve the racemic amine and then recycle the undesired enantiomer. The process is therefore expensive both in terms of capital investment and manpower. Additionally, the load on the waste stream from the washes and salt breaks is extensive, especially from the resolving agent L-pyroglutamic acid.
A key step in the assembly of Compound J is the coupling of the enantiomerically pure piperazine (a) with the enantiomerically pure epoxide (b) to afford the backbone of this important drug for the treatment of HIV infection ((a) Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. Proc. Natl. Acad. Sci. USA 1994, 91, 4096. (b) Idem., J. Med. Chem. 1994, 37, 3443. (c) Askin, D.; Eng, K. K.; Rossen, K.; Purick, R. M.; Wells, K. M.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1994,35, 673. (d) Maligres, P. E.; Upadhyay, V.; Rossen, K.; Cianciosi, S. J.; Purick, R. M.; Eng, K. K.; Reamer; R. A. Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1995, 36, 2195. (e) Maligres, P. E.; Weissman, S. A.; Upadhyay, V.; Cianciosi, S. J.; Purick, R. M.; Eng, K. K; Reamer, R. A.; Sager, J.; Rossen, K.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron 1996,52, 3327. (f) Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P. J. Tetrahedron Lett., 1996, 37, 6843. (g) Rossen, K.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1997, 38, 777). ##STR4##
The preparation of piperazine (a) was previously reported using a chiral hydrogenation of the tetrahydropyrazine (c) (Rossen, K.; Weissman, S. A.; Sager, J.; Reamer, R. A.; Askin, D. A.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1995, 36, 6419). While the chiral hydrogenation occurs in high yield and high ee using the Rh-BINAP catalyst, the synthesis of the tetrahydropyrazine hydrogenation substrate (c) requires 5 steps and thus makes this approach non-competitive with the classical resolution approach (Askin, D.; Eng, K. K.; Rossen, K.; Purick, R. M.; Wells, K. M.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1994, 35, 673). ##STR5##
The synthesis of the heterocycle tetrahydropyrazine is achieved from readily available starting materials using an approach analogous to a previously reported piperazine-2-carboxamide synthesis, where a number of differently substituted piperazine-2-carboxamides were prepared (The Ugi-4-component condensation between chloroacetaldehyde, a carboxylic acid, an isocyanide and a mono-alkyl ethylenediamine gives (d) in a simple one pot reaction in acceptable yields. ##STR6## Rossen, K.; Sager, J.; DiMichele, L. M. Tetrahedron Lett. 1997, 38, 3183. (b) Ugi, I.; Lohberger, S.; Karl, R. in Comprehensive Organic Chemistry: Selectivity for Synthetic Efficiency, Vol. 20. (Eds. B. M. Trost, C. H. Heathcock), Pergamon, Oxford 1991, P. 1083).
Chiral hydrogenation of simple acyclic alpha-(acylamino)acrylic acids and their methyl esters is a known reaction that can occur with high chemical (&gt;95%) and optical yield (&gt;95%) with Rh-chiral bisphosphine catalysts [R. Noyori, Asymmetric Catalysis in Organic Chemistry, John Wiley and Sons, New York, 1994; M. Burk, et al., J. Am. Chem. Soc. 1993, 115, 10125]. Unfortunately, chiral hydrogenation of more complex systems is less successful, and both conversion and optical yield drop off dramatically [H. Brunner, et al., Chem. Ber. 1992, 125, 2085; J. Armstrong, et al., Tetrahedron Lett. 1994, 35, 3239]. Substrates with an olefin as part of a vinylogous urea such as in 1 have not been successfully chirally hydrogenated. It is novel and unexpected to find that the chiral hydrogenation of 9 to 10 described in this invention works in high chemical and optical yield.
The present invention is set forth in Scheme II, concerning a novel process for the preparation of the piperazine intermediate 10 for the production of HIV protease inhibitor compound J. The essential step is accomplished by chirally hydrogenating the partially unsaturated tetrahydropyrazine derivative 9 with a chiral bisphosphine catalyst such as rhodium 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, to the fully saturated piperazine 10. Simple deprotection of the formyl group leads to the intermediate 1. Both the substitution pattern of 9 and choice of catalyst are essential to obtain the high chemical and optical yield. ##STR7##
The chiral hydrogenation of the present invention builds up the desired chiral center from a readily accessible starting material in one step in high chemical and optical yield.